Synthesis and structure activity relationships of potent new angiotensin converting enzyme inhibitors containing saturated bicyclic amino acids

Abstract

The synthesis of a series of novel, potent angiotensin converting enzyme (ACE) inhibitors containing saturated bicyclic amino acids in place of proline is described. Octahydroindole-2-carboxylic acid, octahydroisoindole-1-carboxylic acid, and octahydro-3-oxoisoindole-1-carboxylic acid can replace proline in both sulfhydryl and non-sulfhydryl ACE inhibitors to give compounds equipotent to captopril and enalapril both in vitro and in vivo. Structure-activity relationships are discussed. Compound 11a (CI-907, indolapril) has advanced to clinical evaluation.

β-Lactams or γ-lactams by 4-exo-trig or 5-endo-trig anionic cyclisation of lithiated acrylamide derivatives

“…Cyclic unsaturated amides (entries 5 and 6) cyclise to yield fused 6,5-ring systems, though attempted formation of a 5,5-fused system from 8g failed. The cyclised product 9f bearing the N-cumyl group (-CMe 2 Ph) could be deprotected in acid, 9,14,15 and reprotection and oxidation gave the protected form 14 of a known 16 bicyclic amino acid (Scheme 4). Two balkylated compounds, 8h and 8i, failed to give significant yields of cyclised products; the isomerised amides isolated from the reaction mixture suggest that the main reaction pathway from Cyclisation of the b-phenylthioacrylamide 8j gave directly the unsaturated lactam 10 by elimination of phenylthiolate.…”

Practical access to the proline analogs (S,S,S)‐ and (R,R,R)‐2‐methyloctahydroindole‐2‐carboxylic acids by HPLC enantioseparation

“…However, according to the literature, 18,19 the catalytic hydrogenation of the indole system requires harsh reaction conditions (high temperatures and pressures of hydrogen gas). Yet, some ester derivatives of 8 have been reported 20 to undergo hydrogenation under Rh/C catalysis and hydrogen pressure at room temperature.…”

Synthesis of [c]‐Fused Bicyclic Proline Analogues

“…Racemic octahydroisoindole‐1‐carboxylate 45a has been synthesized by hydrogenation of the isoindole precursor (Scheme ) 13. The use of rhodium on charcoal as a catalyst provided a single stereoisomer in good yield after recrystallization.…”

“…More lipophilic bicyclic proline analogues that bear a saturated ring fused to the [ c ] face of the pyrrolidine make up the core structures of compounds under investigation for potential applications in diseases characterized by joint cartilage damage 12. These analogues have also found application in structure–activity relationship studies for the design of inhibitors of angiotensin‐converting enzyme,13 hepatitis C virus NS3 protease14 and rhinovirus 3C protease,15 which are associated with hypertension, hepatitis and human rhinovirus infections, respectively. In addition, cis ‐methano‐ L ‐proline is a component of peptidomimetic inhibitors of the transcription factor Stat3, an attractive target for anticancer drug design,16 and both stereoisomers of methano‐ L ‐proline are growth‐inhibitory to bacteria 17.…”